Derivatives of acetic acid

ABSTRACT

This disclosure relates to derivatives of acetic acid, e.g., (pbiphenylyloxy)-(p-chlorophenoxy)acetic acid methyl ester. These compounds are useful as hypocholesteremics/hypolipemics.

United States Patent Griot 5] *Au l, 1972 [54] DERIVATIVES OF ACETICACID [56] References Cited [72] Inventor: Rudolf G. Griot, Florham Park,NJ. UNITED STATES PATENTS [731 Assignw Hanover 3,462,446 8/1969 De Wald..260/295 Notice; The onion of the term of this 3,470,234 9/1969 Bencze..260/473 patenlasubsequem to 8 1987, 3,476,767 11/1969 Bencze..260/326.3

l has been dlsc almed Primary Examiner-Henry R. Jiles Flledl 06L 1963Assistant Examiner-G. Thomas Todd Attorney-Gerald D. Sharkin, FrederickH. Weinfeldt, [21] Appl' 768381 Robert S. Honor, Walter F. Jewell andRichard E.

Villa [52] US. Cl.....260/293.82, 260/239 D, 260/239 BF,

260/247.2 B, 260/268 R, 260/268 PH, [57] ABSTRACT g f igg g Thisdisclosure relates to derivatives of acetic acid, 424/267 424/274:424/308 e.g., (p-biphenylyloxy)-(p-chlorophenoxy)acetic acid I C67! 2924 methyl ester. These compounds are useful as [51] C o uhypocholesteremicslhypolipemicsl [58] Field of Search ..260/294.3 A

3 Claims, No Drawings DERIVATIVES OF ACETIC ACID This invention relatesto derivatives of acetic acid. In particular, the invention pertains tobis-(substituted phenoxy) acetic acids and derivatives thereof whichpossess hypocholesteremic/hypolipemic activity. The invention furtherrelates to pharmaceutical compositions containing the above compounds asanactive ingredient thereof and the use of such compositions for thetreatment of hypercholesteremia/hyperlipemia.

The compounds of the present invention are of the structural formulawherein R represents hydrogen or the residue of a monohydric alcoholcapable of forming an ester by reaction with an acid,

e.g. a saturated aliphatic alcohol, preferably a saturated loweraliphatic alcohol such as aliphatic alcohol having 1-5 carbon atoms,e.g. methanol, ethanol, propanol, isopropanol, butanol and the like;.anunsaturated aliphatic alcohol such as alkyl alcohol; a substitutedaliphatic alcohol such as ethanolamine; an aromatic alcohol other than aphenol such as 'benzyl or phenylethylalcohol; an alicyclic alcohol suchas cyclohexanol; a heterocyclic alcohol such as furfuryl alcohol analcohol of the formula B-Ol-l where B represents piperidino, cyanomethylor di[carb(lower)alkoxymethyl, where lower qualifies the alkoxy moietyto mean one containing l-S carbon atoms, an alcohol of the formulaA-Ol-l wherein A (the point of attachment being at either the 2- of 3-positions);

CHCOOR (the point of attachment being at either the 2-, 3- i or4-p0sitions) (the point of attachment being at either the 2- or 3-positions);

(the point -of attachment being at either the 2- or 3- l 0 positions)(the point of attachment being at either the 2-, 3- or 4-positions) or2-dimethylamine-:2-methyl propyl; represents (the point of attachmentbeing at either the 2- or 3- positions);

(the point of attachment being at either the 2- or 3- positions);

(the point of attachment being at either the 2- or 3- positions) 0 4E R5NJ (the point of attachment being at, either the 2- 01' 3- positions)nrepresents a whole number from 1 to 4 inclusive;

each R, independently, represents hydrogen or lower alkyl, preferablycontaining from one to four carbon atoms, e.g., methyl, ethyl, propyland butyl;

nrepresents 2, 3 2,3 4;

R represents hydrogen; halo, preferably bromo or chloro; or lower alkyl,preferably containing from one to four carbon atoms, e.g., methyl,ethyl, propyl and butyl; R represents lower alkyl, preferably containingfrom one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl;propargyl; phenyl; halophenyl, the halo substitutent preferably beingbromo or chloro; or phenyl(lower)alkyl, the lower alkyl substituentpreferably containing from one to four carbon atoms, e.g., benzyl andphenethyl;

R represents hydrogen; lower alkyl, preferably containing from one tofour carbon atoms, e.g., methyl, ethyl, propyl and butyl; cycloalkylcontaining from five to seven ring carbon atoms, e.g., cyclopentyl,cyclohexyl and cycloheptyl; phenyl; phenyl(lower) alky1, the lower alkylsubstituent preferably containing from one to four carbon atoms, e.g.,benzyl and phenethyl; lnaphthyl; or Z-naphthyl; and R represents loweralkyl, preferably containing from one to four carbon atoms, e.g.,methyl, ethyl, propyl and butyl; cycloalkyl containing from five toseven ring carbon atoms, e.g., cyclopentyl, cyclohexyl and cycloheptyl;phenyl; or phenyl(lower)alkyl, the lower alkyl substituent preferablycontaining from one to four carbon atoms, e.g., benzyl and phenethyl;provided that when R is hydrogen R is phenyl,

R R R and R each independently, represents hydrogen, chloro, iodo orbromo, and

R and R each additionally, independently, represents trifluoromethyl orphenyl (which term for purposes of the definition of the compounds offormula (I) in the specification and in the claims is also intended toinclude p-chlorophenyl, p-iodophenyl and pbromophenyl), provided 1. atleast one of the R, and r is other than hydrogen,

2, R R R and R each, independently, may represent only chloro orhydrogen only when R represents other than hydrogen, a residue of asaturated aliphatic alcohol, the basic radical A defined above,piperidino, cyanomethyl or di[carb(lower)alkoxy]methyl,

3. R R R and R each, independently, represents only hydrogen, chloro,iodo or bromo, provided at least one represents other than chloro, onlywhen R represents other than hydrogen or a residue of a saturatedaliphatic alcohol,

4. R and R each, independently, represents trifluorornethyl or phenylonly a. when at least one of R R R and R represents chloro, fluoro oriodo,

b. when one of R, and R represents a trifluorornethyl or phenyl groupand the other of 5 R, and R represents the second group, or

c. when R represents other than hydrogen, A as defined above, or theresidue of a saturated aliphatic alcohol.

It will be clear that the term residue of a monohydric alcohol" is meantthat moiety of the alcoho] other than the -OH portion.

As illustrative of the substituents represented by A there may bementioned the following:

l-lower alkyl-4-piperidyl, e.g., l-methyl-4-piperidyl andl-ethyl4-piperidyl; l-lower alkyl-3-piperidyl, e.g.,--methyl-3-piperidyl and l-ethyl-3-piperidyl; l-lower aIkyl-Z-piperidyl,e.g,, l-methyl-Z-piperidyl and lethyI-Z-piperidyl; l-phenyl-4-piperidyl;l-phenyl-3- piperidyl; l-phenyl-Z-piperidyl; l-benzyl-4-piperidyl; l-benzyl-3-piperidyl; l phenethyl-4-piperidyl; i phenethyl-3-piperidyl;l-propargyl- 4-piperidyl; l-propargyl-3-piperidyl;1-[B-(p-chlorophenoxy)ethyl1-4- piperidyl; 3-quinuclidinyl;Z-quinuclidinyl; B-pyrrolidinoethyl; y-pyrrolidinopropyl;B-piperidinoethyl; "y-piperidinopropyl; fi-morpholinoethyl;ymorpholinopropyl; fi-dimethylaminoethyl; ydiethylaminopropyl',B-anilinoethyl; 'y-anilinopropyl; [3- (N-rnethylanilino)ethyl; B(l-loweralkyl-2-pyrrolidinyl)ethyl, e.g., B-( l-methyl-2-pyrrolidinyl)ethyl; y-(1- lower alkyl-2-pyrrolidinyl)propyl, e.g., 'y-( l-methyl-Z-pyrrolidinyl)propyl, B-( l-phenyl-3-pyrrolidinyl)ethyl; B-(l-phenyl-2-pyrrolidinyl)ethyl; B-( l-beyzyl-3-pyrrolidinyl)ethyl;B-(l-benzyl-2-pyrrolidinyl)ethyl; B-( lphenethyl-3-pyrrolidinyl)ethyl; Bl-phenethyl-Z-pyrrolidinyl)ethyl; fi-( l-propargyl-3-pyrrolidinyl)ethyl;B- (l-propargyl-2-pyrrolidinyl)ethyl; and [Hl-[B-(pchlorophenoxy)ethyl]-3-pyrrolidinyl]ethyl.

The compounds of formula (I) may be prepared according to the processesindicated below.

(VII) halogenatiou CH0 0 OR CHCOUR where R, R R R and R, are as definedabove, and X represents halo, preferably chloro or bromo.

Method A pertains to the reaction of a substituted phenoxy halo aceticacid derivative (II) and an ap propriately substituted phenol (lil) asthe phenolate. This reaction is conveniently effected in a suitableinert organic solvent such as dimethylacetamide; diethylacetamide;dimethylforrnamide; and tetramethylurea. Preferably, the reaction isinitially carried out at room temperature and then allowed to continueat elevated temperatures up to about 80C. The particular solventemployed is not critical, nor is the temperature employed criticalprovided it does not exceed about 80C. The resulting acetic acidderivative (I) is readily recovered employing conventional techniques.The substituted phenol (III) is converted to the phenolate usingstandard techniques, such as treating the phenol with either a strongalkali metal hydroxide, e.g., KOH or NaOH, and water or sodium hydridein dimethylacetamide.

Method B involves the reaction of the substituted phenol (IV) as aphenolate and a dihalocarboxylic acid or derivative thereof (V) and thesolvents and temperatures which may be used are substantially asdiscussed with respect to method A.

The compounds (I) where R represents the basic radical A earlierdescribed may be preferably obtained by treating the compounds offormula (I) where R H or lower alkyl with an alcohol A OH, where A is asearlier defined, under conventional transesterification conditions. Forinstance, this procedure may be performed in an inert organic solventsuch as benzene, toluene or xylene, in the presence of an alkali metalalkoxide, preferably sodium methoxide or ethoxide, at a temperature ofabout 50l50C, preferably at reflux temperature.

The compounds of formula (I) where R represents piperidino arepreferably prepared from the acid halide of the compounds (I) bytreatment with l-hydroxypiperidine or an appropriate salt thereof ininert solvent, e.g., benzene or toluene, at about room temperature.Preferably also, when R represents cyanomethyl or di[carb(lower)alkoxy]methyl, the free acid is treated with a haloacetonitrile or adialkylhalomalonate, respectively, in inert solvent such astetrahydrofuran or ethyl acetate in the presence of a tertiary aminesuch as triethylamine, preferably at the reflux temperature of thesystem.

The substituted phenoxy haloacetic acid ester starting materials (ll)used for process A described above may be prepared as indicatedaccording to processes C and D. Method C concerns treatment of thephenolate of compound (IV) with a monohaloacetic acid (VI), e.g., chloroacetic acid, to obtain the substituted phenoxy acetic acid of formula(VII). The same solvents and reaction conditions discussed respectingprocesses A and B apply here as well. The compounds of formula (VII) arethen halogenated to provide the compounds of formula (ll) (method D).Conventional halogenating agents such as bromine or chlorine may beemployed. The halogenation is conveniently carried out in a suitableinert organic solvent such as a halocarbon, for instance a chloralkane,e.g., dichloromethane, chloroform, carbontetrachloride, and the like.Preferably, the reaction is initially carried out at room temperatureand then allowed to continue at reflux temperature. However, neither thechoice of solvent nor the temperature used is critical.

Certain of the compounds of formula I have asymmetric centers andtherefore exist as optical isomers. The respective isomers can bereadily separated by conventional techniques or they can be selectivelyprepared employing the desired isomeric form of the alcohol reactant andaccordingly are included within the scope of this invention.

Various of the phenolates and alcohols employed as reactants above areknown and are prepared according to methods disclosed in the literature.Those others not specifically described in the literature are preparedby analogous methods from known materials.

As previously indicated, the compounds of formula (I) are useful becausethey possess pharmacological properties in animals. In particular thesecompounds are useful as hypocholesteremics/hypolipemics, as indicated byactivity in sodium hexobarbital anesthetized rat tested by extractingserum or plasma with isopropanol and noting the cholesterol content. Forsuch usage, the compounds may be administered orally as such or admixedwith conventional pharmaceutical carriers or administered orally in suchforms as tablets, dispersible powders, granules, capsules, syrups andelixirs. Such compositions may be prepared according to any method knownin the art for the manufacture of pharmaceutical compositions, and suchcompositions may contain one or more conventional adjuvants, such assweetening agents, flavoring agents, coloring agents and preservingagents, in order to provide an elegant and palatable preparation.Tablets may contain the active ingredient in admixture with conventionalpharmaceutical excipients, e.g., inert diluents, such as calciumcarbonate, sodium carbonate, lactose and talc, granulating anddisintegrating agents, e.g., starch and alginic acid, binding agents,e.g., starch, gelatin and acacia, and lubricating agents, e.g.,magnesium stearate, stearic acid and talc. The tablets may be uncoatedor coated by known techniques to delay disintegration and adsorption inthe gastro-intestinal tract and thereby provide a sustained action overa longer period. Similarly, suspensions, syrups and elixirs may containthe active ingredient in admixture with any of the conventionalexcipients utilized for the preparation of such compositions, e.g.,suspending agents (methylcellulose, tragacanth and sodium alginate),wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylenesorbitan monooleate) and preservatives (ethyl-p 'hydroxybenzoate).Capsules may contain the active ingredient alone or admixed with aninert solid diluent, e.g., calcium carbonate, calcium phosphate andkaolin.

The compounds of formula (I) where R H may also be utilized ashypocholesteremics/hypolipemics in the form of non-toxicpharmaceutically acceptable salts thereof. As illustrative of such saltsthere may be included the aluminum salt, more specifically, thataluminum salt wherein two hydroxyl groups of Al(OH) have been replacedby the acid radical; non-toxic alkali metal salts, e.g., potassium andsodium salts; non-toxic alkaline earth metal salts, e.g., magnesium andcalcium salts; salts with N-containing bases such as ammonium salts andpharmaceutically acceptable primary, secondary and tertiary amine salts,e.g., ethanol amine salts, diethanol amine salts, and the like.

When the compounds (I) are basic esters, such as when R represents A asdefined above, the compounds may also be used as the non-toxic acidaddition salt thereof or quaternary salts. The salts are prepared usingconventional techniques.

The dosage of active ingredient employed for the alleviation ofhyperlipemia (hypercholesteremia) may vary depending on the particularcompound employed and the severity of the condition being treated. Ingeneral, satisfactory results are obtained when these compounds areadministered at a daily dosage of from about 0.5 milligrams to about 50milligrams per kilogram of animal body weight. This daily dosage ispreferably given in divided doses and administered two to four times aday, or in sustained release form. For most large mammals, the totaldaily dosage is from about 50-2000 mg, and dosage forms suitable forinternal use comprise from about 12.5 milligrams to about 500 milligramsof active compound in intimate admixture with a solid or liquidpharmaceutically acceptable carrier or diluent. The preferredpharmaceutical compositions from the standpoint of preparation and easeof administration are solid compositions, particularly hard-filledcapsules and tablets containing from 25 milligrams to about 250milligrams of the active ingredient.

The following examples serve to further illustrate the presentinvention. However, it is to be understood that the examples are forpurposes of illustration only and are not intended as in any waylimiting the scope of the invention which is defined in the appendedclaims.

EXAMPLE 1 (p-trifluoromethylphenoxy)-(p-chlorophenoxy)acetic acid, esterwith l-hydroxypiperidine A mixture of 20.2 g. of l-hydroxypiperidine and800 ml. of absolute diethyl ether is stirred and cooled to about C. inan ice-salt bath. To the cooled mixture is then added dropwise withstirring a solution of 33 g. of(p-trifluoromethylphenoxy-(p-chlorophenoxy) acetyl chloride in 400 ml.of absolute diethyl ether, while maintaining the temperature of thereaction mixture between to 0C. with external cooling. After theaddition is completed, the mixture is stirred for an additional minutesand then, while cooling, 400 ml. of a cold saturated solution of sodiumcarbonate is added and the phases separated. The aqueous phase isextracted with 500 ml. of absolute diethyl ether. The combined organicphases are then washed twice with 400 ml. (each) of cold water, driedover anhydrous potassium carbonate and evaporated to dryness. Theresidue is recrystallized from absolute diethyl ether, using somecharcoal as a decolorizing agent, to obtain (p-trifluoromethylphenoxyp-chlorophenoxy )acetic acid, ester with l-hydroxypiperidine.

EXAMPLE 2 acid CIICOOCIIzCN A mixture of 50 g. of(p-biphenylyloxy)-(pchlorophenoxy) acetic acid, 24.2 g. of triethylamineand 18 g. of chloroacetonitrile and 240 ml. of ethyl acetate is refluxedon a steam bath for 24 hours, then filtered and the ethyl acetatesolution extracted once with 500 ml. of water and then twice with 500ml. (each) of 2N hydrochloric acid. The ethyl acetate layer is thendried over sodium carbonate, filtered with charcoal and then evaporated.The residue is crystallized and recrystallized from diethylether-petroleum ether (1:1) and washed with isopropyl ether to obtain(pbiphenylyloxy)-(p-chlorophenoxy)acetic acid cyanomethyl ester.

EXAMPLE 3 (p-iodophenoxy)-(p-chlorophenoxy)acetic aciddicarbethoxymethyl ester A mixture of 50 g. of(p-iodophenoxy)-(pchlorophenoxy) acetic acid, 24.2 g. of triethyiamine,57.3 g. of diethylbromomalonate and 240 ml. of ethyl acetate is refluxedon a steam bath for 24 hours, then filtered and the ethyl acetatesolution extracted once with 500 ml. of water and then twice with 500ml. of 2N hydrochloric acid. The ethyl acetate layer is then dried oversodium carbonate, filtered with charcoal and then evaporated. Theresidue is distilled using a high vacuum diffusion pump and a maximumoil bath temperature of 250C. to obtain (p-iodophenoxy)-(pchlorophenoxy)acetic acid dicarbethoxymethyl ester.

EXAMPLE 4 (p-bromophenoxy 2-chloro-4- trifluoromethylphenoxy) aceticacid methyl ester CHCOOCH:

Step 1. (p-bromophenoxy)-( acetic acid methyl ester Sodium hydride (56.7percent in mineral oil) (47 g.) is washed free from the mineral oil withlow boiling petroleum either and suspended in 750 ml. ofdimethylacetamide. To the suspension is added g. of p-bromophenol in 500ml. of dimethylacetamide as the temperature is maintained at l0-20C. Themixture is stirred for 2 hours and methyl chloro acetate is added. Theresulting mixture is stirred for 5 hours at 80 C. and then at roomtemperature for 72 hours. The resulting mixture is then poured over 2liters of ice water, extracted with 750 ml. of isopropyl ether. Theorganic layer is separated, extracted with cold 1N sodium hydroxide,dried over anhydrous sodium sulfate, filtered and evaporated to provide(p-bromohenoxy)- (acetic acid methyl ester. Step 2. a-bromophenoxyacetic acid methyl ester To 1 liter of carbon tetrachloride is added l80g. of (p-bromophenoxy)acetic acid methyl ester. With stirring at roomtemperature bromine g.) is added dropwise and the mixture is stirred forl7 hours at room temperature. The mixture is washed with 1,500 ml. ofwater and then 500 ml. of cold lpercent aqueous sodium bicarbonate. Theorganic layer is separated, dried over anhydrous sodium sulfate andevaporated to provide a-bromo-p-bromophenoxy acetic acid methyl ester.Step 3. (p-bromophenoxy)-(2-chloro-4- trifluoromethylphenoxy acetic acidmethyl ester To 200 ml. of dimethylacetamide is added 15 g. of 2-ehloro-4-trifluoromethylphenol and the resulting mixture is addeddropwise, with stirring, to a suspension of 4.6 g. of 56.7 percentsodium hydride (which had been washed free of mineral oil with petroleumether) in 100 ml. of dimethylacetamide. The resulting mixture is stirredat room temperature for 90 minutes and 26 g. of a-bromo-p-bromophenoxyacetic acid methyl ester in 50 ml. of dimethylacetamide is added inseveral portions. The mixture is stirred at room temperature for 72hours, then at 50 C. for 30 minutes, poured over 1,500 ml. of ice waterand extracted with 500 ml. of isopropylether. The ether layer isextracted with 100 ml. of cold lN sodium hydroxide, dried over anhydroussodium sulfate, filtered and evaporated to yield(pbromophenoxy)-(2-chloro-4-trifluoromethylphenoxy) acetic acid methylester.

EXAMPLE 5 (p-biphenylyloxy)-(p-chlorophen0xy) acetic acid 1-methyl-4-piperidyl ester A mixture of g. of(p-biphenylyloxy)-(pchlorophenoxy) acetic acid methyl ester, 3.2 g. oflmethyl-4-hydroxypiperidine, 100 ml. of toluene and 0.2 g. of sodiummethoxide is atmospherically distilled until the sump temperaturereaches 150 C. (approximately 30 minutes). The sump temperature ismaintained at 150 C. for an additional 15 minutes and then with the heatoff water-aspirator vacuum is carefully applied until distillationceases. The resulting mixture is cooled to 50 C. and 200 ml. of benzeneis added thereto. The resulting mixture is further cooled to C. and then200 ml. of water is added thereto. The top oily layer is separated,washed first with 200 ml. of water, then with 100 ml. of a saturatedsolution of sodium chloride and then dried over magnesium sulfate andevaporated on a rotary evaporator at approximately 100 mm vacuum. Theresidue is crystallized from 50 ml. of isopropanol to obtain(p-biphenylyloxy)-(pchlorophenoxy) acetic acid l-methyl-4piperidylester.

EXAMPLE 6 Bis-(p-bromophenoxy)acetic acid l-methyl-4-piperidyl ester\CHC o O-O-Cm Br 0 Step A. Preparation of bis-(p-bromophenoxy)aceticacid methyl ester A solution of 25 grams of 4-bromophenol in 200 ml. ofdimethylacetamide is slowly added to a stirring slurry of 9.5 grams ofsodium hydride (56 percent in mineral oil) in 250 ml. ofdimethylacetamide and the mixture stirred at 20 C. for 1 hour.

To the resulting clear solution is added 14 grams ofmethyldichloroacetate in 200 ml. of dimethylacetamide and a catalyticamount of potassium iodide. The reaction mixture is stirred at 20C. for17 hours and then poured over 1 liter of ice water. The mixture is thenextracted with isopropyl ether. The separated ether layer is extractedwith cold 1N sodium hydroxide and the organic phase separated, driedover magnesium sulfate and evaporated to obtain a brown oil whichcrystallizes upon standing. Recrystallization of the resulting producefrom methanol yields bis-(pbromophenoxy)acetic acid methyl ester; m.p.79.5-8 0.5C.

Step B. Preparation of bis-(p-bromophenoxy)acetic acidl-methyl-4-piperidyl ester Bis-(p-bromophenoxy)acetic acid methyl ester,10 grams, is mixed with 10 grams of B-hydropyethylpiperidine, 50 mg. ofsodium methoxide and 10 ml. of toluene. The resulting mixture is thenslowly heated to distill very slowly through a Vigreux column. When thetemperature at the distilling head reaches 1 10C., the reaction mixtureis cooled to 65C. and then evaporated on a rotary evaporator employing12 mm. vacuum and maintaining the temperature between 657OC. The crudeproduct thus obtained is treated with an excess of a 20 percent aqueoussolution of tartaric acid to yield the tartrate salt ofbis-(pbromophenoxy)acetic acid ,B-piperidinoethyl ester. The free baseis obtained by treating the washed tartrate salt with 2N sodiumhydroxide and extracting the base with dichloromethane.

To obtain the hydrochloride salt, the dichloromethane extract is driedover magnesium sulfate, the solvent evaporated and the residueneutralized with an isopropanolic solution of hydrogen chloride (10percent hydrogen chloride gas in isopropyl alcohol).

EXAMPLE 7 (p-biphenylyloxy)-( p-chlorophenoxy )acetic anilinoethyl ester(p-biphenylyloxy)-(p-chlorophenoxy)acetic acid methyl ester, 10 grams,is mixed with 10 grams of B- anilinoethanol, 50 mg. of sodium methoxideand 10 ml. of toluene. The resulting mixture is slowly heated to distillvery slowly through a Vigreux Column. When the temperature at thedistilling head reaches 1 10C., the reaction mixture is cooled to 65C.and then evaporated on a rotary evaporator employing 12 mm. vacuum andmaintaining the temperature between 657OC. The crude product ischromatographed on a Silica Gel Column and the product recovered bywashing the column with benzene. The benzene is then evaporated off toobtain (p-biphenylyloxy)-(pchlorophenoxy)acetic acid ,B-anilinoethylester.

ester /CHC O O CH2CH2N To a mixture of 120 g. ofbis-(p-bromophenoxy)acetic acid methyl ester, 50 g. ofl-(B-hydroxyethyl) pyrrolidine and 200 ml. of benzene is added withstirring 1 g. of sodium methoxide. The resulting mixture is heated at100C. for 1 hour and then cooled to about lS-20C. To the cooled mixtureis added 500 ml. of benzene and 500 ml. of water. The aqueous phase isthen extracted with 500 ml. of benzene and the combined organic layerswashed twice with 500 ml. (each) of water and then evaporated on arotary evaporator. The residue is dissolved in 200 ml. of isopropanol.To the cooled alcohol solution (5C.) is added, with stirring, a solutionof ll percent hydrochloric acid in isopropanol until the pH thereof isl. The resulting mixture is filtered, the filtrate cooled overnight at-5C. The resulting solid material is filtered off and then slurried atreflux with 50 ml. Ligroin. The solids are recovered by filtration, thenslurried at C. with 100 g. of carbon tetrachloride and filtered off toobtain hisp-bromophenoxy )acetic acid B-pyrrolidinoethyl ester.

EXAMPLE 9 Bis-(p-iodophenoxy)acetic ethylanilino)ethyl ester To amixture of 160 g. of bis-(p-iodophenoxy)acetic acid methyl ester, 80 g.of N-ethyl-N-phenylethanolamine and [,000 ml. of toluene is added, withstirring 2 g. of sodium methoxide. The resulting mixture is heated at120C. for 1 hour and then cooled to about 20C. To the cooled mixture isadded 500 ml. of benzene and 500 ml. of water. The resulting mixture isstirred for 15 minutes, the organic phase separated and washed twicewith 500 ml. (each) of water and then evaporated on a rotary evaporatorat 100 mm. vacuum. The residue is dissolved in 500 ml. of isopropanoland the resulting solution cooled to 5C., filtered and the solids washedwith 200 ml. of cold isopropanol. The washed solids are dissolved in 500ml. of isopropanol and the resulting solution treated at reflux with 10g. of charcoal, then cooled and filtered. The filtrate is allowed tostand for 2 weeks at room temperature. The resulting crystallinematerial is recovered by decanting off the solvent, then ground in amortar and slurried at room temperature with 500 ml. of isopropanol. Theresulting mixture is filtered and the solids washed with 200 ml. ofisopropanol to obtain bis-(p-iodophenoxy)acetic acid [3-(N-cthylanilino) ethyl ester.

EXAMPLE l() (p-trilluoromethylphenoxy 2,4-dichlorophcnoxy)acetic acidacid B-(N- CHC OOH CF; 0

Step 1. (p-trifluorornethylphenoxy)acetic acid Sodium hydride (56.7percent in mineral oil) (47 g.) is washed free from the mineral oil withlow boiling petroleum ether and suspended in 750 ml. ofdimethylacetamide. To the suspension is added 81 g. oftrifluoromethylphenol in 500 ml. of dimethylacetamide as the temperatureis maintained at l0-20C. The mixture is stirred for 1 hour and 38 g. ofchloroacetic acid is added. The resulting mixture is stirred for 5 hoursat C. and then at room temperature for 72 hours. The resulting mixtureis then poured over 2 liters of ice water, made acidic with a slightexcess of hydrochloric acid and is extracted with 750 ml. of isopropylether. The organic layer is separated, washed with water, dried overanhydrous sodium sulfate, filtered and evaporated to provide(p-trifluoromethylphenoxy)- acetic acid.

Step 2. a-bromo-p-trifluoromethylphenoxy acetic acid.

To 1 liter of'carbon tetrachloride is added 10 g. of(p-trifluoromethylohenoxy)acetic acid. With stirring at room temperaturebromine (160 g.) is added dropwise and the mixture is stirred for 17hours at room temperature. The mixture poured onto 2 kilograms ofcrushed ice, stirred for 30 minutes and then separated. The organiclayer is washed repeatedly with water and then dried over anhydroussodium sulfate and evaporated to provide a-bromo-ptrifluoromethylphenoxyacetic acid.

Step 3. (p-trifluoromethylphenoxy)-(2,4- dichlorophenoxy)acetic acid To200 ml. of dimethylacetamide is added 16.3 g. of 2,4-dichlorophenol andthe resulting mixture is added dropwise, with stirring, to a suspensionof 9.2 g. of 56.7 percent sodium hydride (which had been washed free ofmineral oil with petroleum ether) in 100 ml. of dimethylacetamide. Theresulting mixture is stirred at room temperature for minutes and 22 g.of abromo-pJrifluoromethylphenoxy acetic acid in 50 ml. ofdimethylacetamide is added gradually. The mixture is stirred at roomtemperature for 72 hours, then at 50C. for 30 minutes, poured over 1,500ml. of ice water, acidified with hydrochloric acid, and extracted with500 ml. of isopropylether. The ether layer is extracted with ml. ofwater, dried over anhydrous sodium sulfate, filtered and evaporated toyield (ptrifluoro-methylphenoxy 2,4-dichlorophenoxy)acetic acid.

When the above procedure is carried out and pchlorophenyl, p-iodophenol,p-bromophenol, p-phenylphenol, p-(p-chlorophenyl phenol or 2,4-dibromophenol is used in place of 2,4-dichlorophenol, there is obtained(p-trifluoromethylphenoxy)-(p-chlorophenoxy)acetic acid,

(p-trifluoromethylphenoxy acetic acid,

( p-trifioromethylphenoxy acetic acid, (p-trifluromethylphenoxy aceticacid, (p-triflouromethylphenoxy p-(p-chlorophenyi )phcnoxy] acetic acid,or (p-trifluoromethylphenoxy 2,4-dibromophcnoxy acetic acid,

respectively.

What is claimed is: l. A compound of the formula R CHCOOA wherein Arepresents (CHR) R,

R represents n represents a whole number of from 1 to 4, inclusive;

each R, independently, represents hydrogen or lower alkyl;

R represents hydrogen, halo or loweralkyl; and

R represents lower alkyl, propargyl, phenyl,

halophenyl or phenyl(lower)alkyl;

R,, R R and R each independently represents hydrogen, chloro, iodo orbromo, and R and R additionally each, independently, representstrifluoromethyl or phenyl, provided I. at least one of R and R is otherthan hydrogen, 2. R R R and R each, independently, may not representonly chloro or hydrogen, 3. R and R each, independently, representstrifluoromethyl or phenyl only a. when at least one of R R a R and Rrepresents chloro, bromo or iodo, or b. when one of R and R represents atrifluoromethyl or phenyl group and the other of R and R represents thesecond group; or a non-toxic acid addition or quaternary salt thereof.

2. The compound of claim 1 which is bis-(pbromophenoxy) acetic acid1-methyI-4-piperidyl ester.

3. The compound of claim 1 which is (p-biphenylyloxy)-(p-chlorophenoxy)acetic acid l-methyl-4- piperidyl ester.

2. The compound of claim 1 which is bis-(p-bromophenoxy) acetic acid1-methyl-4-piperidyl ester.
 2. R2, R2, R3 and R4 each, independently,may not represent only chloro or hydrogen,
 3. R1 and R2 each,independently, represents trifluoromethyl or phenyl only a. when atleast one of R1, R2, a R3 and R4 represents chloro, bromo or iodo, or b.when one of R1 and R2 represents a trifluoromethyl or phenyl group andthe other of R1 and R2 represents the second group; or a non-toxic acidaddition or quaternary salt thereof.
 3. The compound of claim 1 which is(p-biphenylyloxy)-(p-chlorophenoxy) acetic acid 1-methyl-4-piperidylester.